1. Field of the Invention
The present invention relates generally to nutritional or pharmaceutical compositions and methods of use for the treatment of HIV-associated fat maldistribution and hyperlipidemia.
2. Description of the Related Art
As in the case with many other infections, HIV infection is accompanied by disturbances in lipid and glucose metabolism. These metabolic abnormalities are further confounded by hypercholesterolemia and hypertriglyceridemia induced by anti-retroviral (AR) drugs. It has been estimated that almost two-thirds of HIV/AIDS patients exhibit abnormal fat distribution coincident with AR-therapy (ART). Clinicians have termed this abnormal fat distribution lipodystrophy or fat maldistribution. Although various terms have been used, the term both lipodystrophy and fat maldistribution will be used here interchangeably to describe the syndrome of body shape changes related to changes in fat distribution in people with HIV/AIDS receiving AR-therapy (HIV/ART).
Various descriptions have been proposed for the morphologic abnormalities and the metabolic alterations that appear to be associated with fat maldistribution. While clinicians have a general understanding of changes in fat distribution occurring in persons with HIV, no consensus exists among them on the clinical measures used to define fat maldistribution. When questioned, physicians generally describe a syndrome of “maldistribution of body fat,” “buffalo hump,” “thinning of arms and legs,” “facial thinning,” and/or “increases in abdomen size.” Few physicians mention metabolic markers when defining fat maldistribution.
“Lipo” refers to fat and “dystrophy” means abnormal growth. Before being recognized in HIV-infected patients, the lipodystrophies were described as rare abnormalities of adipose tissue characterized by body shape changes and metabolic abnormalities, including insulin resistance, hyperglycemia, and hyperlipidemia.
Although there appear to be some similarities between the established lipodystrophies seen prior to HIV and that seen in HIV/ART patients, there is little evidence of fat accumulation or maldistribution as being a common presentation in persons with lipodystrophy before the development of successful ART combinations for HIV. The fat maldistribution with HIV/AR-related lipodystrophy is typically a mix of central fat accumulation and peripheral fat loss, and this pattern does not seem to fit readily into any definition of previously described lipodystrophies.
Historically, before HIV, lipodystrophy was used to describe features of lipoatrophy only. The use of this term to describe features of fat accumulation as well as fat loss in HIV/ART-patients helped to initiate the confusion, which still exists, on the clinical case definition of HIV/ART-related lipodystrophy. Nevertheless, it is now accepted that the lipodystrophy seen in patients with HIV infection receiving ART is a syndrome involving physical and metabolic abnormalities.
The physical changes associated with the HIV/ART lipodystrophy syndrome can be divided into two major types, both of which involve an abnormal or maldistribution of body fat: lipoatrophy or fat wasting and lipohypertrophy or fat accumulation. An increase in abdominal girth is a common complaint in patients, while thinning of the extremities is also frequently seen, often with prominence of the veins in the arms and legs (cabling) due to subcutaneous fat loss. A substantial proportion of patients report increased wrinkling of the skin with a loss of subcutaneous tissue in the cheeks and around the nose and lips.
Abnormal metabolic changes include altered lipid metabolism manifest by increased triglycerides, increased total cholesterol and increased low-density lipoprotein (LDL) cholesterol. Alterations in glucose metabolism with lipodystrophy include insulin resistance, impaired glucose tolerance and type 2 diabetes.
Although surgery is sometimes elected to remove unsightly fat deposits and restore normal facial appearance, the most frequently prescribed drugs for maintaining normal body composition are recombinant human growth hormone (Somatotrophin®) and anabolic steroids (e.g. Oxandrin®). Other adjunctive measures, such as progressive resistance exercises may also be utilized. Cosmetic surgery appears to be only a stopgap measure and patients frequently continue abnormal body fat deposition. The medications described are highly effective in many patient groups. However, human growth hormone is costly and anabolic steroids may present significant hepatic and cardiovascular risk to the HIV patient.
Among the dietary supplements sold to promote body composition changes, N-acetylcysteine (NAC), L-carnitine, acetyl-L-carnitine, arginine and omega-3 fatty acids have been suggested for wasting and lipodystrophy in HIV/AIDS. No positive data have yet been developed to support these recommendations.
The role of NAC in HIV has been examined since 1989 in 16 peer-reviewed publications (Breitkreutz R, et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials [see comments]. J Mol Med 2000; 78(1):55-62; Akerlund B, et al. N-acetylcysteine treatment and the risk of toxic reactions to trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients. J Infect 1997; 35:143-147; Jahoor F, et al. Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Am J Physiol 1999; 276:E205-E211; Walmsley S L, et al. A randomized trial of N-acetylcysteine for prevention of trimethoprim-sulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). Canadian HIV Trials Network 057 Study Group. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19(5):498-505; Look M P, et al. Sodium selenite and N-acetylcysteine in antiretroviral-naive HIV-1-infected patients: a randomized, controlled pilot study. Eur J Clin Invest 1998; 28:389-397; Herzenberg L A, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 1997; 94:1967-1972; Akerlund B, et al. Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. Eur J Clin Pharmacol 1996; 50:457-461; Witschi A, et al. Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. AIDS Res Hum Retroviruses 1995; 11:141-143; de Quay B, et al. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992; 6:815-819; De Rosa S C, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2000; 30:915-929; Muller F, et al. Virological and immunological effects of antioxidant treatment in patients with HIV infection. Eur J Clin Invest 2000; 905-914; Kinscherf R, et al. Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells. FASEB J 1994; 8:448-451; Bogden J D, et al. Status of selected nutrients and progression of human immunodeficiency virus type 1 infection. Am J Clin Nutr 2000; 72:809-815; Skurnick J H, et al. Micronutrient profiles in HIV-1-infected heterosexual adults. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12:75-83; Bogden J D, et al. Micronutrient status and human immunodeficiency virus (HIV) infection. Ann N Y Acad Sci 1990; 587:189-195]. Due to its history of safe use as a therapeutic, NAC has been suggested as a potential supplement for glutathione replenishment in HIV since 1991 (Droge W, et al. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med 1991; 91:140 S-144S; Mihm S, et al. Inhibition of HIV-1 replication and NF-kappa B activity by cysteine and cysteine derivatives. AIDS 1991; 5:497-503; Harakeh S, and Jariwalla R J. Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. Am J Clin Nutr 1991; 54:1231 S-1235S). While NAC has demonstrated several positive effects for people living with HIV, no research studies have reported that treatment of HIV-infected persons with NAC alone, or in combination with other nutrients or drugs, can successfully ameliorate fat maldistribution or hyperlipidemia.
Research on fatty acids in HIV has been generally limited and only one clinical trial has been reported on HIV wasting and fatty acid supplementation. A combination consisting of omega-3 fatty acids and arginine was clinically tested for its ability to affect weight gain and blood lipid levels in HIV/ART patients (Sudre, P C, et al. A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and omega-3 fatty acids in HIV-infected patients. Swiss HIV Cohort Study. AIDS 12(1)53-63). Sixty-four HIV-infected outpatients with CD4 counts greater than or equal to 100/μL were randomized to receive 7.4 g arginine plus 1.7 g omega-3 fatty acids or placebo daily. Gain in body weight and fat mass were approximately 2 and 1 kg, respectively in both treatment and placebo groups. Thus, enrichment of an oral nutritive supplement with arginine and omega-3 fatty acids did not improve weight gain or fat-free mass in HIV/ART patients. Such results imply that fatty acid supplementation alone, or in certain obvious combinations, are unlikely to positively affect fat distribution or hyperlipidemia in HIV/ART patients.
In conclusion, metabolic disorders such as hyperlipidemia and hyperglycemia are prevalent among HIV-infected individuals receiving ART. Morphological changes accompany these metabolic disorders and have been termed lipodystrophy syndrome. Affected individuals show fat redistribution, such as fat loss (e.g., in face) or fat accumulation (e.g., in abdominal area). These metabolic disorders are generally attributed to ART. Left untreated, the downstream adverse consequences of fat maldistribution include atherogenesis and atherosclerotic vascular disease. Thus, there is a critical need to provide nutritional supplementation to manage these metabolic and morphologic disorders. At this time, there are no safe and efficacious nutritional products that can normalize metabolic or body changes in HIV/ART-patients.